7. Project Summary/Abstract Opioid drugs are effective pain-relievers that elicit analgesia through their action at brain -opioid receptors, simultaneously activating rewarding brain pathways, which can lead to opioid tolerance and drug dependence. The U.S. has the highest world-wide per capita use of opioids creating enormous health and societal costs related to addiction and treatment, lost productivity, and increased crime. Response to opioid drugs varies widely between people, and potentially between genders, but it is not clear why people experience different levels of pain relief from the same opioid, and why some people progress to become addicted. Many opioids are activated to even more potent -opioid receptor agonists by CYP2D enzymes, such as oxycodone that is converted to oxymorphone. However, oxymorphone is transported out of the brain and body more rapidly than oxycodone, hence oxycodone is responsible for analgesia. This project uses unique research methods to investigate how metabolism of opioids by CYP2D enzymes in the brain is important in oxycodone, tramadol and hydrocodone response. Both liver and brain CYP2D levels are regulated by genetics, but in addition, brain CYP2D is very sensitive to environmental chemicals, notably nicotine. Therefore, there can be two individuals who have the same CYP2D activity in the liver (same genetics) but very different levels of CYP2D activity in the brain, e.g. through smoking. Their drug and metabolite blood levels may be similar, but metabolism by brain CYP2D can alter oxycodone levels in the brain, influencing pain relief, tolerance and abuse liability. ?How does variation in oxycodone metabolism by CYP2D in the brain affect oxycodone analgesia and reward?? Validated rat models of analgesia, tolerance and reward, will be used with drug and dopamine microdialysis, pharmacokinetic modelling, and established methods of manipulating brain but not liver CYP2D levels. Brain CYP2D will be reduced by injecting chemical inhibitors into the brain, and increased by chronic systemic nicotine treatment. Decreased brain CYP2D should increase analgesia, tolerance and reward through reduced oxycodone conversion to oxymorphone, resulting in higher brain oxycodone levels. Increased brain CYP2D should decrease analgesia, tolerance and reward through greater metabolism of oxycodone to oxymorphone, resulting in lower brain oxycodone levels. Plasma oxycodone and metabolites levels will not change as liver CYP2D is unaffected by these manipulations. Two additional CYP2D substrates, the commonly prescribed oral opioids, hydrocodone and tramadol, and sex differences in oxycodone responses will also be investigated. This will improve mechanistic understanding of this novel source of variation between people in their opioid response, and identification of individuals at risk for opioid pain-treatment failure and progression to dependence on these widely used oral opioids. Extensive PB-PK modelling will assist in extrapolations to human, as will planned human PET imaging studies. The knowledge acquired from this project will contribute to our on-going efforts to reduce the societal and health costs of opioid drug misuse and dependence.